Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults

Abstract

Summary:Topotecan appears to be relatively unaffected by the most common multidrug resistance mechanisms, may potentiate cytotoxicity of alkylators, has good penetration into the central nervous system, is active against a variety of neoplasms, and has myelosuppression as its paramount toxicity. We present our experience with a myeloablative regimen that includes topotecan. Twenty-one patients with poor-prognosis tumors and intact function of key organs received topotecan 2 mg/m 2 by 30-min intravenous (i.v.) infusion on days −8, −7, −6, −5, −4; thiotepa 300 mg/m 2 by 3 h i.v. infusion on days −8, −7, −6; and carboplatin by 4 h i.v. infusion on days −5, −4, −3 with a daily dose derived from the pediatric Calvert formula, using a targeted area under the curve of seven mg/ml* min (ෂ500 mg/m 2 /day). Stem cell rescue was on day 0. The patients were 1 to 29 (median 4) years old; 18 were in complete remission (CR) and three in partial remission (PR). Early toxicities were severe mucositis and erythema with superficial peeling in all patients and a seizure, hypertension, and renal insufficiency followed by veno-occlusive disease in one patient each. Post-transplant treatment included radiotherapy alone (four patients) or plus biological agents (11 patients with neuroblastoma). With a follow-up of 6+ to 32+ (median 11+) months, event-free survivors include 10/11 neuroblastoma patients (first CR), 4/5 brain tumor patients (second PR or CR), 1/3 patients with metastatic Ewing's sarcoma (first or second CR), and a patient transplanted for multiply recurrent immature ovarian teratoma; a patient with desmoplastic small round-cell tumor (second PR) had progressive disease at 8 months. Favorable results for disease control, manageable toxicity, and the antitumor profiles of topotecan, thiotepa, and carboplatin, support use of this three-drug regimen in the treatment of neuroblastoma and brain tumors; applicability to other tumors is still uncertain. Bone Marrow Transplantation (2001) 28, 551-556.

Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system

“…(Nine patients were included in the report on preliminary results with this regimen. 13 ) Eligibility requirements included adequate function of kidneys (creatinine clearance X60 ml/min/1.73 m 2 ), heart, and liver (p1.5 Â normal levels of serum transaminases and bilirubin), and informed written consent in accordance with hospital rules.…”

“…We used all three agents at dosages identified in phase I-II studies as safe and effective: thiotepa achieved significantly better results at X900 mg/m 2 , with doselimiting CNS toxicity at 1125 mg/m 2 ; 27 carboplatin had impressive antitumor activity at X1200 mg/m 2 and was safe in dosages up to 2000 mg/m 2 ; 29 and topotecan 10 mg/m 2 divided over 5 days became a commonly used salvage treatment because of impressive anticancer activity and modest toxicity, 11,13 though lower dosages were used in conventional combination chemotherapy regimens. [30][31][32][33][34] The 3 days of thiotepa preceded the 3 days of carboplatin, and the 5 days of topotecan were completed before the last dose of carboplatin.…”

“…We previously reported preliminary results with the same regimen, used against a variety of solid tumors. 13 Only one other report has appeared on a topotecan-containing myeloablative regimen for NB. 14 …”

High-Dose Chemotherapy in Childhood Brain Tumors

“…Carboplatinum was added to this combination (BCNU/thiotepa/carbo/VP16 [22]) in multiple courses in 3 pediatric patients, showing feasibility despite the expected toxicity. Far less toxic is the combination of thiotepa (300 mg/m 2 / d ×3d) with carboplatinum (500 mg/m 2 /d ×3d) and topotecan (2 mg/m 2 /d ×5d) [44]. The response rate of 4/5 brain tumors is encouraging and warrants more studies with this combination.…”

A new multidrug reinduction protocol with topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine for relapsed or refractory acute leukemia

“…20,21 Additionally, the combination of thiotepa, topotecan, and carboplatin followed by autologous SCT offers a favorable antitumor effect for pediatric solid tumors. 22 Vinorelbine is a semisynthetic Vinca rosea alkaloid. 23,24 Early in vitro data suggest that vinorelbine may have a role in the treatment the acute leukemias, although it appears to be less active in acute myeloblastic leukemia (AML) when compared to acute lymphoblastic leukemia (ALL).…”